This invention relates to the field of processes for synthesizing chiral substituted N-aryl piperazine compounds to provide compounds that bind to the 5HT receptors in the central nervous system and intermediates therefor.
Some N,Nxe2x80x2 disubstituted piperazines, specifically those with N-aryl substitution, act on the central nervous system (e.g., bind to 5HT receptors). The J. Med. Chem. (1995), 38(20), 4044-55 and JP 61152655 teach the conventional approach to synthesize the aryl piperazine core, which involves reacting anilines with bis(dichloroethyl)amine. The resulting piperazines are elaborated by alkylating the resulting secondary amine. 
A xe2x80x9creversedxe2x80x9d version of this chemistry is also possible. In this approach, an aniline mustard-like intermediate reacts with an alkyl amine, as shown, for example, in J. Labeled Compounds and RadioPharm. (1986) Vol XXIV, No. 4, 351. However, the commercial availability of bis(2-cholorethyl)amine hydrochloride relative to the general availability of aniline mustards makes this approach less attractive. 
Asymmetric aryl piperazines are also formed by coupling piperazines with aryl triflates or bromides. Tetrahedron Letters (1998), 39, 2219 indicates that yields for this process are very (aryl) substrate dependent and generally are low. 
The formation of piperazines bearing a chiral center directly on nitrogen is the present invention""s focus. Some methods for the formation of chiral N-piperazines are known. One known method is to resolve a racemic mixture, which has the disadvantage of wasting half the material.
Another known method is to displace a leaving group attached to a chiral center with an aryl piperazine. The barrier to displacement of the hindered leaving group is a problem, however. Enhancing the leaving group""s reactivity creates other problems: JP 01125357 teaches that benzyl-(S)-bromopropionate reacts with 1-benzylpiperazine to give the expected (R) isomer displacement product. The carbonyl group, while activating the displacement process, also increases the susceptibility of the adjacent chiral center toward racemization under the reaction conditions.
WO 95/33743 reports an alternative that eliminates the racemization problem of activation by utilizing a chiral cyclic sulfamate as the reactive alkylating agent. 
While cyclic sulfamates react readily with piperazines, the sulfamate itself requires numerous steps to prepare. In the case where R=2-pyridyl, for example, four separate chemical steps or transformations are required.
In Acta Pol. Pharm., 56 (1), 41-47; 1999 it is reported that chiral amino acids reacting with N-methyl-N,N-bis(2-chloroethane). The carboxylic acid function makes the chiral center susceptible to racemization both during the reaction and during subsequent synthetic manipulations.
In another approach, J. Med Chem. 30(10), 1779-87; 1987 reports chiral benzyl amines react with a variety of mustards, both N-alkyl and N-aryl. The chiral amines employed were obtained by resolution.
WO94/24115 teaches the reaction of xcex2-alkyl(and aryl)oxy chiral amines with mustards to form piperazine compounds.
To date, most syntheses of N-aryl Nxe2x80x2 substituted piperazines involve preforming the N-aryl piperazine followed by alkylation on Nxe2x80x2. This approach is an efficient way to prepare many compound types. However, it is of limited practicality for the introduction of chirality xcex1 to the nitrogen because it relies on chiral alkylating agents that require multi-step syntheses to prepare.
The present invention comprises a process for preparing a compound of formula VII 
wherein
R is C1-C3 alkyl,
Y is C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkoxy, and
Ar is 2,3-dihydro-benzodioxin-5-yl, or phenyl optionally substituted with up to three substituents independently selected from halogen, methoxy, halomethyl, dihalomethyl and trihalomethyl,
said process comprising:
a) reacting a compound of formula III with a chiral 2-amino-1-(C3-C5)alkanol in a polar aprotic solvent to form a compound of formula IV 
wherein L represents a leaving group selected from Cl, Br, mesylate and tosylate, and * indicates a chiral center;
b) converting the compound of formula IV to a compound of formula V 
wherein X is Cl, Br, triflate, tosylate or mesylate; and,
c) treating the compound of formula V with a compound of formula VI in an aprotic solvent 
wherein M is an alkali metal (e.g., Na, Li, K) and Y represents a moiety selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl and C3-C7 cycloalkoxy.
This invention further comprises a process for making a compound of formula IX comprising steps (a), (b) and (c) above plus the steps of:
(d) treating the compound of formula VII with a protic acid to form a compound of formula VIII 
and, (e) treating the compound of formula VIII with an aroyl compound selected from aroyl chloride, aroyl bromide and aroyl anhydride, in the presence of a base, to form a compound of formula IX 
wherein Aryl represents a C6-C12 aromatic group optionally substituted with up to three substituents independently selected from the group consisting of halogen atoms, alkyl, alkoxy, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl, dihaloalkyl, trihaloalkyl, nitrile and amido substituents each having no more than six carbon atoms.
A preferred embodiment of the present invention is a process for making N-aryl piperazines with chiral Nxe2x80x2-1-[benzoyl(2-pyridyl)amino]-2-propane side-chains, which bind at the 5HT receptor. Another embodiment of this invention is a process for making intermediate compounds therefor. In the process of this invention, chirality is introduced at the piperazine ring formation step.
In a preferred embodiment of this invention, the synthesis begins with the creation of a dimesylate compound of formula III by first dialkylating an aniline of formula I with chloroethanol to form diol of formula II. Alternatively, the diol compound of formula II is prepared by dialkylation of the aniline with an alkyl haloacetate followed by reduction. The two hydroxyl groups are conveniently converted into suitable leaving groups, such as mesylate leaving groups: 
The dimesylate reacts with a chiral 2-amino-1-propanol (alaninol) to give the desired piperazine. In other embodiments of this invention, the chiral amino compound is 2-amino-1-butanol, 2-amino-1-pentanol, or 2-amino-3-methyl-1-butanol. Leaving groups other than mesylate may be used in the practice of this invention, including tosylate, chloro and bromo. The chirality of the amine component is preserved in the process. The alcohol group, which requires no protection during the cyclization, is poised for further structural elaboration. The resulting primary alcohol is then activated for displacement by, for example, treatment with methane sulfonyl chloride or bromide. This reaction is believed to form a mesylate which is a transient intermediate, and results in a compound of formula V. 
In a preferred embodiment of this invention, the compound of formula V reacts with the anion derived from 2-(t-Boc)-aminopyridine to introduce an aminopyridyl side chain and produce a compound of formula VII. 
It is also within the scope of this invention to use other groups in place of the tert-butoxy group; suitable groups include C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl and C3-C7 cycloalkoxy. Where this group is one of the aforesaid cyclic groups, one or more of the carbon atoms may be outside the cyclic ring, for example, cyclohexylmethoxy or ethylcyclopentyl.
The compound of formula VII can be further reacted to form compounds of formulae VIII and IX. Preferably, the t-Boc protecting group is removed with HCl/EtOH to form the amine of formula VII as an HCl salt. The salt can be used directly for functionalization of the free NH group. While the embodiment illustrated below indicates acylation with aroyl chlorides, other acyl derivatives may be used in the practice of this invention. 
Since the present synthesis incorporates chirality during the piperazine forming step, a chiral amine is all that is required. The reaction is surprisingly very efficient even in the presence of a nearby free hydroxyl group (e.g., III IV). 
The hydroxyl group can then be used as a handle to introduce aminopyridyl functionality via displacement. It is not apparent on the surface or from the prior art how seriously the side reactions described above can threaten the usefulness of this displacement. Much depends on the specific alkylating reagent. In WO9703982, an aminopyridine VIa, under unspecified conditions, can be reacted with generic compounds Va, where X is a leaving group, to give VIIa. In the course of developing this invention, we observed that the anion of alkyl acyl compounds (i.e., VIb) when reacted with V (X=Cl) gave a significant quantity (ca. 20%) of undesired alkylation on the pyridyl nitrogen, forming compound X. In a preferred embodiment of the present invention, Y is an alkoxy group.
This invention provides a practical synthesis of N-aryl piperazines where chirality is introduced at the piperazine ring formation step and 2-aminopyridyl substitution is incorporated via displacement.
The use of t-Boc 2-amino pyridine, VI, as described in this invention significantly suppresses the amount ( less than 7%) of analogous by-product formed, increasing the proportion of desired compound VII. As shown in the preceding section, the t-Boc protecting group is easily removed and the freed amine can then acylated.
Throughout this specification and in the appended claims, except where otherwise indicated, the terms halogen and halo refer to F, Cl and Br, and the terms alkyl, alkane, alkanol and alkoxy include both straight and branched chain alkyl groups.
The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.